Neurotransmitter is stored in the synaptic vesicle in the pre-synaptic terminal prior to its release in the synaptic cleft upon depolarization of the pre-synaptic membrane. The release of the neurotransmitter is a multi-step process that is controlled by electrical signals passing through the axons in form of action potential. Neurotransmitters include glutamate, acetylcholine, nor-epinephrine, dopamine and seratonin. Each of the neurotransmitter cycle is independently described.
View original pathway at Reactome.
Binda F, Dipace C, Bowton E, Robertson SD, Lute BJ, Fog JU, Zhang M, Sen N, Colbran RJ, Gnegy ME, Gether U, Javitch JA, Erreger K, Galli A.; ''Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux.''; PubMedEurope PMCScholia
Jen JC, Wan J, Palos TP, Howard BD, Baloh RW.; ''Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.''; PubMedEurope PMCScholia
Quesada AR, Sanchez-Jimenez F, Perez-Rodriguez J, Marquez J, Medina MA, Nuñez de Castro I.; ''Purification of phosphate-dependent glutaminase from isolated mitochondria of Ehrlich ascites-tumour cells.''; PubMedEurope PMCScholia
Sun L, Bittner MA, Holz RW.; ''Rim, a component of the presynaptic active zone and modulator of exocytosis, binds 14-3-3 through its N terminus.''; PubMedEurope PMCScholia
Takamori S, Riedel D, Jahn R.; ''Immunoisolation of GABA-specific synaptic vesicles defines a functionally distinct subset of synaptic vesicles.''; PubMedEurope PMCScholia
Barclay JW, Craig TJ, Fisher RJ, Ciufo LF, Evans GJ, Morgan A, Burgoyne RD.; ''Phosphorylation of Munc18 by protein kinase C regulates the kinetics of exocytosis.''; PubMedEurope PMCScholia
Buddhala C, Hsu CC, Wu JY.; ''A novel mechanism for GABA synthesis and packaging into synaptic vesicles.''; PubMedEurope PMCScholia
Hong SB, Li CM, Rhee HJ, Park JH, He X, Levy B, Yoo OJ, Schuchman EH.; ''Molecular cloning and characterization of a human cDNA and gene encoding a novel acid ceramidase-like protein.''; PubMedEurope PMCScholia
Riento K, Galli T, Jansson S, Ehnholm C, Lehtonen E, Olkkonen VM.; ''Interaction of Munc-18-2 with syntaxin 3 controls the association of apical SNAREs in epithelial cells.''; PubMedEurope PMCScholia
Henry JP, Botton D, Sagne C, Isambert MF, Desnos C, Blanchard V, Raisman-Vozari R, Krejci E, Massoulie J, Gasnier B.; ''Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules.''; PubMedEurope PMCScholia
Melone M, Varoqui H, Erickson JD, Conti F.; ''Localization of the Na(+)-coupled neutral amino acid transporter 2 in the cerebral cortex.''; PubMedEurope PMCScholia
Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA.; ''Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.''; PubMedEurope PMCScholia
Stein A, Radhakrishnan A, Riedel D, Fasshauer D, Jahn R.; ''Synaptotagmin activates membrane fusion through a Ca2+-dependent trans interaction with phospholipids.''; PubMedEurope PMCScholia
Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H.; ''Cloning and characterization of two human polyspecific organic cation transporters.''; PubMedEurope PMCScholia
Bak LK, Schousboe A, Waagepetersen HS.; ''The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer.''; PubMedEurope PMCScholia
Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH.; ''Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.''; PubMedEurope PMCScholia
Lin CI, Orlov I, Ruggiero AM, Dykes-Hoberg M, Lee A, Jackson M, Rothstein JD.; ''Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18.''; PubMedEurope PMCScholia
Butz S, Okamoto M, Südhof TC.; ''A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.''; PubMedEurope PMCScholia
Sun L, Bittner MA, Holz RW.; ''Rab3a binding and secretion-enhancing domains in Rim1 are separate and unique. Studies in adrenal chromaffin cells.''; PubMedEurope PMCScholia
Mueller HT, Borg JP, Margolis B, Turner RS.; ''Modulation of amyloid precursor protein metabolism by X11alpha /Mint-1. A deletion analysis of protein-protein interaction domains.''; PubMedEurope PMCScholia
Gómez-Fabre PM, Aledo JC, Del Castillo-Olivares A, Alonso FJ, Núñez De Castro I, Campos JA, Márquez J.; ''Molecular cloning, sequencing and expression studies of the human breast cancer cell glutaminase.''; PubMedEurope PMCScholia
Iioka H, Moriyama I, Kyuma M, Ito K, Amasaki M, Ichijo M.; ''[Studies on L-glutamate transport mechanism in human placental trophoblast microvilli membrane vesicles].''; PubMedEurope PMCScholia
Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N.; ''Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase.''; PubMedEurope PMCScholia
Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR.; ''A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs.''; PubMedEurope PMCScholia
Augustin I, Rosenmund C, Südhof TC, Brose N.; ''Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles.''; PubMedEurope PMCScholia
Johnson RG.; ''Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport.''; PubMedEurope PMCScholia
Elgadi KM, Meguid RA, Qian M, Souba WW, Abcouwer SF.; ''Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing.''; PubMedEurope PMCScholia
Okuda T, Haga T.; ''Functional characterization of the human high-affinity choline transporter.''; PubMedEurope PMCScholia
Gopalakrishnan A, Sievert M, Ruoho AE.; ''Identification of the substrate binding region of vesicular monoamine transporter-2 (VMAT-2) using iodoaminoflisopolol as a novel photoprobe.''; PubMedEurope PMCScholia
Zhou Y, Danbolt NC.; ''Glutamate as a neurotransmitter in the healthy brain.''; PubMedEurope PMCScholia
Michaelson DM, Angel I.; ''Determination of delta pH in cholinergic synaptic vesicles: its effect on storage and release of acetylcholine.''; PubMedEurope PMCScholia
Khvotchev M, Dulubova I, Sun J, Dai H, Rizo J, Südhof TC.; ''Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 N terminus.''; PubMedEurope PMCScholia
Toonen RF, de Vries KJ, Zalm R, Südhof TC, Verhage M.; ''Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation.''; PubMedEurope PMCScholia
Toussaint JL, Geoffroy V, Schmitt M, Werner A, Garnier JM, Simoni P, Kempf J.; ''Human choline acetyltransferase (CHAT): partial gene sequence and potential control regions.''; PubMedEurope PMCScholia
Apparsundaram S, Ferguson SM, George AL, Blakely RD.; ''Molecular cloning of a human, hemicholinium-3-sensitive choline transporter.''; PubMedEurope PMCScholia
Becherer U, Rettig J.; ''Vesicle pools, docking, priming, and release.''; PubMedEurope PMCScholia
Schoch S, Gundelfinger ED.; ''Molecular organization of the presynaptic active zone.''; PubMedEurope PMCScholia
de Vrij W, Bulthuis RA, van Iwaarden PR, Konings WN.; ''Mechanism of L-glutamate transport in membrane vesicles from Bacillus stearothermophilus.''; PubMedEurope PMCScholia
Dulubova I, Khvotchev M, Liu S, Huryeva I, Südhof TC, Rizo J.; ''Munc18-1 binds directly to the neuronal SNARE complex.''; PubMedEurope PMCScholia
Rilstone JJ, Alkhater RA, Minassian BA.; ''Brain dopamine-serotonin vesicular transport disease and its treatment.''; PubMedEurope PMCScholia
Erickson JD, Varoqui H, Schäfer MK, Modi W, Diebler MF, Weihe E, Rand J, Eiden LE, Bonner TI, Usdin TB.; ''Functional identification of a vesicular acetylcholine transporter and its expression from a "cholinergic" gene locus.''; PubMedEurope PMCScholia
Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, Kavanaugh M, Edwards RH.; ''Glutamine uptake by neurons: interaction of protons with system a transporters.''; PubMedEurope PMCScholia
Takamori S, Rhee JS, Rosenmund C, Jahn R.; ''Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons.''; PubMedEurope PMCScholia
Glutamate synaptic vesicle contains Rab3 ( GTPase), synaptobrevin/VAMP ( V-SNARE), VGLUT1 (Glutamate transporter) and synpatotagmin which is beleived to be a Ca2+ sensor and plays a role in the synaptic vesicle fusion process.
Acetylcholine synaptic vesicle contains Rab3 ( GTPase), synaptobrevin/VAMP ( V-SNARE), VGLUT1 (Glutamate transporter) and synpatotagmin which is beleived to be a Ca2+ sensor and plays a role in the synaptic vesicle fusion process.
GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. GABA modulates neuronal excitability throughout the nervous system. Disruption of GABA neurotransmission leads to many neurological diseases including epilepsy and a general anxiety disorder. GABA is synthesized by two distinct enzymes GAD67 and GAD65 that differ in their cellular localization, functional properties and co-factor requirements. GABA synthesized by GAD65 is used for neurotransmission whereas GABA synthesized by GAD67 is used for processes other than neurotransmission such as synaptogenesis and protection against neuronal injury. GABA is loaded into synaptic vesicle with the help of vesicular inhibitory amino acid transporter or VGAT. GAD65 and VGAT are functionally linked at the synaptic vesicle membrane and GABA synthesized by GAD65 is preferentially loaded into the synaptic vesicle over GABA synthesized in cytoplasm by GAD67.The GABA loaded synaptic vesicles are docked at the plasma membrane with the help of the SNARE complexes and primed by interplay between various proteins including Munc18, complexin etc. Release of GABA loaded synaptic vesicle is initiated by the arrival of action potential at the presynaptic bouton and opening of N or P/Q voltage gated Ca2+ channels. Ca2+ influx results in Ca2+ binding by synaptobrevin, which is a part of the SNARE complex that also includes SNAP25 and syntaxin, leading to synaptic vesicle fusion. Release of GABA in the synaptic cleft leads to binding of GABA by the GABA receptors and post ligand binding events.
Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Munc 18 interacts with syntaxin in the plasma membrane, with Mint (Munc 18 interacting) which in turn interacts with CASK and neurexins. Munc18 also interacts with granulophilin. Granulophilin is interacts simultaneously with syntaxin and Munc18. These interactions are believed to be involved in the docking of the synaptic vesicle to the plasma membrane. However, the sequence of events is unclear.
Munc 18 interacts with syntaxin in the plasma membrane, with Mint (Munc 18 interacting) which in turn interacts with CASK and neurexins. Munc18 also interacts with granulophilin. Granulophilin is interacts simultaneously with syntaxin and Munc18. These interactions are believed to be involved in the docking of the synaptic vesicle to the plasma membrane. However, the sequence of events is unclear.
There are two classes of glutamate transporters; the excitatory amino acid transporters (EAATs) which depend on an electrochemical gradient of Na+ ions and vesicular glutamate transporters (VGLUTs) which don't. Together, these transporters uptake and release glutamate to mediate this neurotransmitter's excitatory signal and are part of the glutamate-gluatamine cycle. The SLC1 gene family includes five high-affinity glutamate transporters encoded by SLC1, 2, 3, 6 and 7. These transporters can mediate transport of L-Glutamate (L-Glu), L-Aspartate and D-Aspartate with cotransport of 3 Na+ ions and H+ and antiport of a K+ ion. This mechanism allows glutamate into cells against a concentration gradient thus excess L-Glu released by the pre-synaptic neuron in the synaptic cleft is cleared. This is a crucial factor in the protection of neurons against glutamate excitotoxicity in the CNS. SLC1A2 and 3 are mainly expressed by astrocytes whereas SLC1A1 and 6 are predominantly neuronal. SLC1A1 is expressed throughout the CNS however SLC1A6 is predominantly localized to purkinje cells. SLC1A7 is highly expressed in rod photoreceptor and bipolar cells of the retina. Astrocytic SLC1As are expressed in astrocytes in close apposition to the synapses and neuronal SLC1As are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic SLC1As are responsible for majority of the glutamate uptake, neuronal transporters are responsible for glutamate clearance in specialized synapses in cerebellum where the spatial relationship between the glutamate receptors and SLC1As is altered and glutamate receptors are expressed in the peri-synaptic region (Zhou & Danbolt 2014). Defects in the SLC1A1 gene may be a cause of dicarboxylicamino aciduria (glutamate-aspartate transport defect in the kidney and intestine) (Jen et al. 2005). PRA1 family protein 3 (ARL6IP5 aka ADP-ribosylation factor-like protein 6-interacting protein 5) is a microtuble-associated protein that is able to regulate intracellular concentrations of glutamate as well as tuarine. It negatively regulates SLC1A1 by decreasing its affinity for glutamate (L-Glu). The activity of human SLC1A1 is based on similarity to rat Eaac1 (aka GTRAP3-18) (Lin et al. 2001).
Docking occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.
Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the glutamate into the synaptic cleft.
Nascent synaptic vesicles are loaded with glutamate by VGLUT1 to form glutamate containing synaptic vesicles. This process occurs while the synaptic vesicle is in the cytosol.
Glutamine in neurons is transported into mitochondrial matrix by an unknown transporter (Chaudhry et al. 2002). Because this enzyme is not yet identified, it is represented as a black box event.
Glutamate from the mitochondrial matrix is transported back into the cytosol, to be loaded into synaptic vesicles. Solute carrier 25 is a mitochondrial glutamate transporter known to transport glutamate, but it is unclear if this protein is involved in the transport of glutamate in neurons (Iioka et al. 1995).
Acetylcholine is actively transported from the cytosol to the lumen of the synaptic vesicle by vesicular acetylcholine transporter. Two protons are exchanged for 1 molecule of acetylcholine. The vesicular acetylcholine transporter is located in the membrane of the synaptic vesicle.
Docking and priming of acetylcholine loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming reaction have been worked out using synaptic vesicles loaded with glutamate and similar reactions may occur during the transport cycle of acetylcholine. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.
Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q, R, and L type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the acetylcholine into the synaptic cleft.
Dopamine is transported from the cytosol into the reacidified clathrin sculpted monoamine transport vesicle by membranous vesicular monoamine transporter
Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the noradrenalin into the synaptic cleft.
Noradrenaline is degraded by Monoamine oxidase A, which contains FAD as a cofactor. Monoamine oxidase is located in the outer mitochondrial membrane facing the cytoplasmic site. Monoamine xoidase functions as a monomer and is functional both is astrocyes and neurons.
Docking and priming of clathrin sculpted Noradrenaline loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming recation have been worked out using synaptic vesicle loaded with glutamate and similar reactions may occur during the transport cycle of noradrenaline. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.
Dopamine loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasma membrane. The docking brings the vesicles in close proximity to the release site to facilitate the release of dopamine. Some of the molecules involved in the docking process are STXBP1 (Munc 18), RAB3A (Rab3), RIMS1 (Rab 3 interacting molecule, RIM), BZRAP1 (RIM-binding protein), UNC13B (Munc13) and alpha-liprins.
STXBP1 is an SM (Sec1/Munc18-like) protein that probably functions by wrapping around the trans-SNARE complex to catalyze membrane fusion. It binds to the amino-terminus of STX1A (syntaxin-1A) (Dulubova et al. 1999) and though it's exact role is unclear (Sudhof & Riso 2011), it is essential for membrane fusion in vivo (Khvotchev et al. 2007).
During synaptic exocytosis synaptic vesicles dock with an electron-dense structure called the presynaptic active zone. This has at least four key protein components: UNC13B, RIMS1, BZRAP1 and alpha-liprins. UNC13B is essential for synaptic priming (Augustin et al. 1999). The amino-terminal zinc-finger domain of RIMS1 interacts with the amino-terminal C2a-domain of UNC13B (Lu et al. 2006). A proline-rich domain in RIMS1 interacts with an SH3 domain in BZRAP1 (Wang et al. 2000). Alpha-liprins bind the C2B domain of RIMS1 (Schoch et al. 2002). RIMS1 binds to synaptic vesicle-bound RAB3A (Lu et al. 2006) and possibly SYT1 (synaptotagmin). RIMS1 and BZRAP1 bind to N and P/Q-type calcium channels in the plasma membrane (Kaeser et al. 2011).
The priming reaction brings docked but unprimed synaptic vesicles into a releasable pool. Priming involes formation of the trimeric SNARE complex between two plasma membrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.
The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft.
The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft.
Serotonin loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of serotonin. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.
The human SLC5A7 gene encodes a sodium- and chloride-dependent, high affinity choline transporter, CHT (Apparsundaram et al. 2000). CHT transports choline (Cho) from the extracellular space into neuronal cells and is dependent on Na+ and Cl- ions for transport (Okuda & Haga 2000). Choline uptake is the rate-limiting step in acetylcholine synthesis.
In brain, a complex of three proteins form a tripartite complex which may act to couple synaptic vesicle exocytosis to neuronal cell adhesion. Any of the three protein lin7 homologs A, B or C (LIN7A,B or C) can bind to amyloid beta A4 precursor protein-binding family A member 1 (APBA1 aka MINT1) and peripheral plasma membrane protein CASK (aka LIN2) (Butz et al. 1998). All of these proteins contain PDZ domains, not used in complex formation thus able to recruit adhesion molecules, receptors and channels to the complex.
N-acylethanolamines (NAEs) are bioactive lipid molecules present in animals and plants. N-acylethanolamine-hydrolyzing acid amidase (NAAA), a heterodimeric lysosomal enzyme is able to hydrolyse NAEs to their respective fatty acids (FAs) and ethanolamine (ETA). The NAEs N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, and N-oleoylethanolamine possess cannabimimetic activity, anti-inflammatory and analgesic activities, and anorexic activity, respectively. NAAA can mediate their endogenous levels and shows greatest affinity for N-palmitoylethanolamine (Hong et al. 1999, Tsuboi et al. 2005).
Mitochondrial glutaminase (GLS) catalyzes the hydrolysis of glutamine to yield glutamate and ammonia. Two GLS enzymes have been identified, one abundantly expressed in the liver (GLS - Elgadi et al. 1999) and one abundantly expressed in kidney (GLS2 - Gomez-Fabre et al. 2000). Their biochemical properties are similar. The enzymes are inferred to function as dimers based on unpublished crystallographic data for GLS (PDB 3CZD) and studies of glutaminase enzyme purified from Ehrlich Ascites cells (Quesada et al. 1988).
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Loaded Synaptic
Vesicleloaded synaptic
vesicleloaded Synaptic
Vesicleloaded synaptic
vesicleloaded synaptic
vesiclerelease, reuptake
and degradationAnnotated Interactions
Loaded Synaptic
VesicleLoaded Synaptic
VesicleLoaded Synaptic
Vesicleloaded synaptic
vesicleloaded synaptic
vesicleloaded synaptic
vesicleloaded Synaptic
Vesicleloaded Synaptic
Vesicleloaded Synaptic
Vesicleloaded synaptic
vesicleloaded synaptic
vesicleloaded synaptic
vesicleloaded synaptic
vesicleloaded synaptic
vesicleloaded synaptic
vesicleSLC1A1 is expressed throughout the CNS however SLC1A6 is predominantly localized to purkinje cells. SLC1A7 is highly expressed in rod photoreceptor and bipolar cells of the retina. Astrocytic SLC1As are expressed in astrocytes in close apposition to the synapses and neuronal SLC1As are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic SLC1As are responsible for majority of the glutamate uptake, neuronal transporters are responsible for glutamate clearance in specialized synapses in cerebellum where the spatial relationship between the glutamate receptors and SLC1As is altered and glutamate receptors are expressed in the peri-synaptic region (Zhou & Danbolt 2014).
Defects in the SLC1A1 gene may be a cause of dicarboxylicamino aciduria (glutamate-aspartate transport defect in the kidney and intestine) (Jen et al. 2005).
PRA1 family protein 3 (ARL6IP5 aka ADP-ribosylation factor-like protein 6-interacting protein 5) is a microtuble-associated protein that is able to regulate intracellular concentrations of glutamate as well as tuarine. It negatively regulates SLC1A1 by decreasing its affinity for glutamate (L-Glu). The activity of human SLC1A1 is based on similarity to rat Eaac1 (aka GTRAP3-18) (Lin et al. 2001).
AcCho is synthesised in the cytoplasm of cholinergic neurons from acetyl-CoA and Cho by CHAT enzyme.
STXBP1 is an SM (Sec1/Munc18-like) protein that probably functions by wrapping around the trans-SNARE complex to catalyze membrane fusion. It binds to the amino-terminus of STX1A (syntaxin-1A) (Dulubova et al. 1999) and though it's exact role is unclear (Sudhof & Riso 2011), it is essential for membrane fusion in vivo (Khvotchev et al. 2007).
During synaptic exocytosis synaptic vesicles dock with an electron-dense structure called the presynaptic active zone. This has at least four key protein components: UNC13B, RIMS1, BZRAP1 and alpha-liprins. UNC13B is essential for synaptic priming (Augustin et al. 1999). The amino-terminal zinc-finger domain of RIMS1 interacts with the amino-terminal C2a-domain of UNC13B (Lu et al. 2006). A proline-rich domain in RIMS1 interacts with an SH3 domain in BZRAP1 (Wang et al. 2000). Alpha-liprins bind the C2B domain of RIMS1 (Schoch et al. 2002). RIMS1 binds to synaptic vesicle-bound RAB3A (Lu et al. 2006) and possibly SYT1 (synaptotagmin). RIMS1 and BZRAP1 bind to N and P/Q-type calcium channels in the plasma membrane (Kaeser et al. 2011).
The priming reaction brings docked but unprimed synaptic vesicles into a releasable pool. Priming involes formation of the trimeric SNARE complex between two plasma membrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.